PB2391: FREQUENCY OF IKZF3 MUTATION IN WALDENSTRÖM’S MACROGLOBULINEMIA
Authors: Assia Taleb, Raphaël Van der Veen, Carole Fleury, Florence Cymbalista, Fanny Baran-Marszak, Gregory Lazarian
Journal: HemaSphere (2023)

Topic: 20. Lymphoma Biology & Translational Research Background: A mutation of the transcription factor AIOLOS/IKZF3, a member of the IKAROS family, has been identified as a putative driver of chronic lymphocytic leukemia (CLL) through large-scale WES studies of CLL patients, with a frequency of ~3% CLLs. The mutation has been detected uniquely as a hotspot mutation (p.L162R, exon 5), localized within the DNA binding domain, conferring a gain-of-function by altering DNA binding specificity and expression of IKZF3 target genes, resulting in overexpression of B-cell receptor (BCR) signaling genes. Aims: Apart from CLL, IKZF3 mutations are rarely described in Waldenström Macroglobulinemia (WM). In this study, we aimed to evaluate the frequency of IKZF3 mutations in lymphoproliferative B cell disorders reported in the literature and to screen the hotspot mutation IKZF3 L162R in a large cohort of patients with WM. Methods: A droplet digital PCR assay was optimized to detect the IKZF3 L162R mutation with a high sensitivity in a retrospective cohort of 78 patients harboring a mutation of MYD88. Targeted NGS sequencing of 13 genes frequently mutated in lymphoid malignancies was performed for patients harboring the IKZF3 mutation. Results: By analyzing the frequencies of all IKZF3 variants reported in the literature and through the cBioPortal and COSMIC databases, 43 IKZF3 mutated cases were reported mostly in lymphoid neoplasia, with 45% of the IKZF3 mutations reported in CLL and 35% in diffuse large B cell lymphoma. Interestingly, the hotspot IKZF3 L162R affecting the DNA binding domain is the most frequent mutation reported (35%), suggesting a selection of this gain-of-function mutation and a common mechanism of lymphomagenesis. However, IKZF3 mutations are rarely reported in WM, which could be explained by a low infiltration of the samples by tumoral cells and a lack of sensitivity of the sequencing techniques used. Among the 78 patients tested, the mutation was detected in 5 patients (5/78; 6%) with variant allelic frequencies (VAF) comprised between 0.7% and 2.4%, reflecting the small proportion of circulating tumor cells. Targeted NGS sequencing confirmed the presence of the IKZF3-L162R mutation in samples with VAF >1%. The IKZF3 L162R mutation was found in the same range of VAF as MYD88 mutation in 2 cases and was subclonal in 3 cases. No other additional mutation (including TP53 and CXCR4) was identified by NGS. Four of the IKZF3 mutated cases presented neuropathy complication associated with anti MAG-antibodies for 3 cases. The other complications included anemia (2 cases), hyperviscosity (1 case), cryoglobulinemia (1 case), and chronic inflammation (1 case). Almost all patients with IKZF3 mutation had a symptomatic disease requiring treatment and received either bortezomib-desamethasone-rituximab (2 cases) or ibrutinib-rixutimab (1 case). Treated patients are currently in complete response. Summary/Conclusion: Altogether, IKZF3 L162R mutation is as common in WM as in CLL. The presence of this mutation in various lymphoproliferative B cell disorders suggest a common mechanism of lymphomagenesis related to the dysregulation of BCR-signaling genes. More samples including marginal zone lymphoma are currently sequenced to better appreciate the distribution of this mutation among B cell lymphomas. Keywords: Lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia